MHC polymorphism under host-pathogen coevolution

The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change.

[1]  R. Zinkernagel,et al.  Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex , 1975, Nature.

[2]  Peter Parham,et al.  HLA-A and B polymorphisms predate the divergence of humans and chimpanzees , 1988, Nature.

[3]  Konrad Beck.  Coevolution: Mathematical analysis of host-parasite interactions , 1984, Journal of mathematical biology.

[4]  P. Parham,et al.  Diversity and diversification of HLA-A,B,C alleles. , 1989, Journal of immunology.

[5]  W. Deppert,et al.  Antiviral protective immunity induced by major histocompatibility complex class I molecule-restricted viral T-lymphocyte epitopes inserted in various positions in immunologically self and nonself proteins , 1995, Journal of virology.

[6]  G. Snell.  The H-2 locus of the mouse: observations and speculations concerning its comparative genetics and its polymorphism. , 1968, Folia biologica.

[7]  Søren Brunak,et al.  Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation , 2002, Journal of Virology.

[8]  C. Lively,et al.  HOST‐PARASITE COEVOLUTION: EVIDENCE FOR RARE ADVANTAGE AND TIME‐LAGGED SELECTION IN A NATURAL POPULATION , 1998, Evolution; international journal of organic evolution.

[9]  John H. Holland,et al.  Adaptation in Natural and Artificial Systems: An Introductory Analysis with Applications to Biology, Control, and Artificial Intelligence , 1992 .

[10]  C. Wills.  Maintenance of Multiallelic Polymorphism at the MHC Region , 1991, Immunological reviews.

[11]  C. Lively,et al.  Parasite adaptation to locally common host genotypes , 2000, Nature.

[12]  J. Klein,et al.  Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans‐species mode of evolution. , 1988, The EMBO journal.

[13]  M. Nei,et al.  Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection , 1988, Nature.

[14]  Andrew J. McMichael,et al.  Common West African HLA antigens are associated with protection from severe malaria , 1991, Nature.

[15]  José A. M. Borghans,et al.  Diversity in the immune system , 2000 .

[16]  José A. M. Borghans,et al.  Heterozygote advantage fails to explain the high degree of polymorphism of the MHC , 2004, Immunogenetics.

[17]  M. Nei,et al.  Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. , 1990, Genetics.

[18]  W. Hamilton,et al.  Sexual reproduction as an adaptation to resist parasites (a review). , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[19]  D. Watkins,et al.  Major histocompatibility complex class I genes in primates: co‐evolution with pathogens , 1999, Immunological reviews.

[20]  R. Slade,et al.  Overdominant vs. frequency-dependent selection at MHC loci. , 1992, Genetics.

[21]  James Theiler,et al.  Advantage of rare HLA supertype in HIV disease progression , 2003, Nature Medicine.

[22]  C. Moore,et al.  Evidence of HIV-1 Adaptation to HLA-Restricted Immune Responses at a Population Level , 2002, Science.

[23]  T. Ohta,et al.  Population Biology of Antigen Presentation by MHC Class I Molecules , 1996, Science.

[24]  M. Nei,et al.  Models of host-parasite interaction and MHC polymorphism. , 1992, Genetics.

[25]  José A. M. Borghans,et al.  Major Histocompatibility Complex: Polymorphism from Coevolution , 2002 .

[26]  W. Potts,et al.  MHC heterozygosity confers a selective advantage against multiple-strain infections , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  F. Black,et al.  Why did they die? , 1992, Science.

[28]  L. Segel,et al.  Design Principles for the Immune System and Other Distributed Autonomous Systems , 2001 .

[29]  W K Potts,et al.  The nature of selection on the major histocompatibility complex. , 1997, Critical reviews in immunology.

[30]  P. Parham,et al.  Diversity of class I HLA molecules: functional and evolutionary interactions with T cells. , 1989, Cold Spring Harbor symposia on quantitative biology.

[31]  A Sette,et al.  Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. , 1994, Journal of immunology.

[32]  R. Lewontin,et al.  Heterosis as an explanation for large amounts of genic polymorphism. , 1978, Genetics.

[33]  W. Bodmer,et al.  Evolutionary Significance of the HL-A System , 1972, Nature.

[34]  M. Nei,et al.  Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Nagylaki.  Introduction to Theoretical Population Genetics , 1992 .

[36]  W. Potts,et al.  The Evolution of Mating Preferences and Major Histocompatibility Complex Genes , 1999, The American Naturalist.

[37]  P Parham,et al.  Evolution of class-I MHC genes and proteins: from natural selection to thymic selection. , 1990, Annual review of immunology.

[38]  B. Korber,et al.  Evolutionary and immunological implications of contemporary HIV-1 variation. , 2001, British medical bulletin.

[39]  A. Lloyd,et al.  The Influence of HLA Class I Alleles and Heterozygosity on the Outcome of Human T Cell Lymphotropic Virus Type I Infection1 , 2000, The Journal of Immunology.

[40]  J. Goedert,et al.  HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. , 1999, Science.

[41]  J. Klein,et al.  Molecular Evolution of the Major Histocompatibility Complex , 2011, NATO ASI Series.

[42]  H. Rammensee,et al.  HLA-A2 subtypes are functionally distinct in peptide binding and presentation , 1995, The Journal of experimental medicine.

[43]  K. Aoki,et al.  A criterion for the establishment of a stable polymorphism of higher order with an application to the evolution of polymorphism , 1980, Journal of mathematical biology.

[44]  P. Hedrick.  PATHOGEN RESISTANCE AND GENETIC VARIATION AT MHC LOCI , 2002, Evolution; international journal of organic evolution.